rs77009095

Variant names:

• chr5-78116244-C-T
• rs77009095
• NM_003664.5:c.1969-10G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003664.5(AP3B1):​c.1969-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0692 in 1,593,932 control chromosomes in the GnomAD database, including 4,256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (326 hom., cov: 32)
  • Exomes 𝑓: 0.071 (3930 hom.)
• Consequence: AP3B1 NM_003664.5 intron
• Scores: Splicing: ADA: 0.0003659
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.179
• Publications: 3 publications found

Genes affected

AP3B1 (HGNC:566): (adaptor related protein complex 3 subunit beta 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is part of the heterotetrameric AP-3 protein complex which interacts with the scaffolding protein clathrin. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2012]

AP3B1 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 5-78116244-C-T is Benign according to our data. Variant chr5-78116244-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0759 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003664.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	NM_003664.5	MANE Select	c.1969-10G>A		intron	N/A	NP_003655.3
	AP3B1	NM_001271769.2		c.1822-10G>A		intron	N/A	NP_001258698.1	O00203-3
	AP3B1	NM_001410752.1		c.1969-10G>A		intron	N/A	NP_001397681.1	A0A8Q3SIM7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.1969-10G>A		intron	N/A	ENSP00000255194.7	O00203-1
	AP3B1	ENST00000519295.7	TSL:1	c.1822-10G>A		intron	N/A	ENSP00000430597.1	O00203-3
	AP3B1	ENST00000913629.1		c.1969-10G>A		intron	N/A	ENSP00000583688.1

Frequencies

GnomAD3 genomes AF: 0.0531 AC: 8077 AN: 152090 Hom.: 327 Cov.: 32

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0530

Gnomad ASJ AF: 0.0793

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0538

Gnomad FIN AF: 0.0688

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0777

Gnomad OTH AF: 0.0660

GnomAD2 exomes AF: 0.0594 AC: 14856 AN: 250254 AF XY: 0.0619

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0374

Gnomad ASJ exome AF: 0.0893

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0690

Gnomad NFE exome AF: 0.0785

Gnomad OTH exome AF: 0.0719

GnomAD4 exome AF: 0.0709 AC: 102280 AN: 1441724 Hom.: 3930 Cov.: 27 AF XY: 0.0711 AC XY: 51103 AN XY: 718722

African (AFR) AF: 0.0118 AC: 391 AN: 33044

American (AMR) AF: 0.0405 AC: 1810 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0893 AC: 2324 AN: 26036

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39526

South Asian (SAS) AF: 0.0560 AC: 4811 AN: 85900

European-Finnish (FIN) AF: 0.0701 AC: 3714 AN: 52996

Middle Eastern (MID) AF: 0.0500 AC: 287 AN: 5740

European-Non Finnish (NFE) AF: 0.0777 AC: 85001 AN: 1094098

Other (OTH) AF: 0.0659 AC: 3934 AN: 59710

GnomAD4 genome AF: 0.0530 AC: 8073 AN: 152208 Hom.: 326 Cov.: 32 AF XY: 0.0529 AC XY: 3935 AN XY: 74414

African (AFR) AF: 0.0129 AC: 535 AN: 41546

American (AMR) AF: 0.0529 AC: 809 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0793 AC: 275 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0541 AC: 261 AN: 4826

European-Finnish (FIN) AF: 0.0688 AC: 728 AN: 10580

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0777 AC: 5280 AN: 67994

Other (OTH) AF: 0.0648 AC: 137 AN: 2114

Alfa AF: 0.0639 Hom.: 132

Bravo AF: 0.0514

Asia WGS AF: 0.0230 AC: 79 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hermansky-Pudlak syndrome (1)
-	-	1	Hermansky-Pudlak syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00037
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs77009095; hg19: chr5-77412068;